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Article

  • The EMBO Journal (2007) 26, 2251 - 2261
  • doi:10.1038/sj.emboj.7601682

Published online: 19 April 2007

Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation

Camilla Hauge1, Torben L Antal1, Daniel Hirschberg2, Ulrik Doehn1, Katrine Thorup1, Leila Idrissova3, Klaus Hansen1, Ole N Jensen2, Thomas J Jørgensen2, Ricardo M Biondi3 and Morten Frödin1

  1. Biotech Research and Innovation Centre, Ole Maaløes vej, Copenhagen N, Denmark
  2. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej, Odense, Denmark
  3. Research Group PhosphoSites, Department of Internal Medicine II, University of Saarland, Homburg, Germany

Correspondence to:

Morten Frödin, The Kinase Signalling Group, Biotech Research and Innovation Centre, Ole Maaløes vej 5, Copenhagen N 2200, Denmark. Tel.: +45 35 32 56 54; Fax: +45 35 32 56 69; E-mail: morten.frodin@bric.dk

Received 21 February 2006; Accepted 19 March 2007

The growth factor/insulin-stimulated AGC kinases share an activation mechanism based on three phosphorylation sites. Of these, only the role of the activation loop phosphate in the kinase domain and the hydrophobic motif (HM) phosphate in a C-terminal tail region are well characterized. We investigated the role of the third, so-called turn motif phosphate, also located in the tail, in the AGC kinases PKB, S6K, RSK, MSK, PRK and PKC. We report cooperative action of the HM phosphate and the turn motif phosphate, because it binds a phosphoSer/Thr-binding site above the glycine-rich loop within the kinase domain, promoting zipper-like association of the tail with the kinase domain, serving to stabilize the HM in its kinase-activating binding site. We present a molecular model for allosteric activation of AGC kinases by the turn motif phosphate via HM-mediated stabilization of the alphaC helix. In S6K and MSK, the turn motif phosphate thereby also protects the HM from dephosphorylation. Our results suggest that the mechanism described is a key feature in activation of upto 26 human AGC kinases.

  • Keywords:

    • AGC kinase,
    • growth factor,
    • PKB,
    • RSK,
    • S6K